In the aging population, lower urinary tract (LUT) dysfunction is common and often leads to storage and voiding difficulties classified into overlapping symptom syndromes. Despite prevalence and consequences of these syndromes, LUT disorders continue to be undertreated simply because there are few therapeutic options. LUT function and structure were assessed in aged (>25 months) male and female Fischer 344 rats randomized to oral treatment with a purine nucleoside phosphorylase (PNPase inhibitor) 8-aminoguanine (8-AG) or vehicle for 6 weeks. The bladders of aged rats exhibited multiple abnormalities: tactile insensitivity, vascular remodeling, reduced collagen-fiber tortuosity, increased bladder stiffness, abnormal smooth muscle morphology, swelling of mitochondria, and increases in urodamaging purine metabolites. Treatment of aged rats with 8-AG restored all evaluated histological, ultrastructural, and physiological abnormalities toward that of a younger state. 8-AG is an effective treatment that ameliorates key age-related structural and physiologic bladder abnormalities. Because PNPase inhibition blocks metabolism of inosine to hypoxanthine and guanosine to guanine, likely uroprotective effects of 8-AG are mediated by increased bladder levels of uroprotective inosine and guanosine and reductions in urodamaging hypoxanthine and xanthine. These findings demonstrate that 8-AG has translational potential for treating age-associated LUT dysfunctions and resultant syndromes in humans.
Lori A. Birder, Amanda Wolf-Johnston, Alan J. Wein, Fangzhou Cheng, Mara Grove-Sullivan, Anthony J. Kanai, Alan M. Watson, Donna Stoltz, Simon C. Watkins, Anne M. Robertson, Diane Newman, Roger R. Dmochowski, Edwin K. Jackson
Title and authors | Publication | Year |
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Purine nucleoside phosphorylase inhibition- a novel approach for the treatment of chemical hemorrhagic cystitis
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Hypoxanthine Induces Signs of Bladder Aging With Voiding Dysfunction and Lower Urinary Tract Remodeling.
Birder LA, Wolf-Johnston AS, Zabbarova I, Ikeda Y, Robertson AM, Cardozo R, Azari F, Kanai AJ, Kuchel GA, Jackson EK |
The journals of gerontology. Series A, Biological sciences and medical sciences | 2024 |
Oral 8-aminoguanine against age-related retinal degeneration
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Research square | 2024 |
Purine nucleoside phosphorylase as a target for the treatment of interstitial cystitis/bladder pain syndrome with and without Hunner lesions.
Birder LA, Wolf-Johnston A, Ritov V, Stern JNH, Moldwin R, Kuo HC, Jackson EK |
Scientific reports | 2024 |
8-Aminopurines: A Promising New Direction for Purine-Based Therapeutics.
Jackson EK, Tofovic SP, Chen Y, Birder LA |
Hypertension (Dallas, Tex. : 1979) | 2024 |
Effect of Collagen Fiber Tortuosity Distribution on the Mechanical Response of Arterial Tissues
Agrawal Y, Fortunato RN, Asadbeygi A, Hill MR, Robertson AM, Maiti S |
Journal of Biomechanical Engineering | 2024 |